This is a request for an NIDCD K08 Mentored Clinical Scientist Development Award for Jay A. Gottfried, MD, PhD, under the mentorship of Dr. M.-Marsel Mesulam, MD, Professor of Neurology, Northwestern University, and the co-mentorship of Dr. Lawrence Marks, PhD, Professor of Psychology, Yale University. Clarifying the biological links between physical and perceptual attributes of odor is a critical issue in olfactory neuroscience. Why does one volatile organic compound "smell" like chocolate, and another like cheese? There has been little systematic research to address these questions. The long-term objective of the proposed project is to understand the nature of odor coding in the human brain. Functional neuroimaging techniques will be combined with olfactory paradigms of cross-adaptation, perceptual learning, and classical conditioning to characterize the neural response properties of primary olfactory (piriform) cortex. These studies will be complemented by olfactory psychophysics approaches to assess the behavioral influence of sensory experience and associative learning on odor quality perception and discrimination. - As part of the career development plan, Dr. Gottfried will learn new skills in human olfactory psychophysics (Dr. Marks), gain additional training in neuroimaging (Drs. Apkarian, Gitelman, Parrish), and receive supervision in behavioral neuroscience (Dr. Mesulam) and clinical neuropsychology (Dr. Weintraub), all complemented by didactic instruction in sensory information theory, statistics, experimental design, and MRI physics. The knowledge acquired during this project should allow Dr. Gottfried to develop into an independent clinician-investigator in human olfaction specializing in functional imaging applications that span the interface between basic olfactory neuroscience and clinical behavioral neurology. Abnormalities in the sense of smell figure prominently in a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Therefore, a systematic understanding of olfactory function in healthy subjects may lead to new insights concerning the pathophysiology, diagnosis, and perhaps even treatment of these neurodegenerative conditions. By helping to clarify how smells are represented in the intact human brain, the proposed research may have important utility in enlightening our understanding of Alzheimer's disease and other neurological disorders.